Neuropeptide TIP39 induces autophagy in PTH2 receptor-positive myeloid neoplasms.

Neuropeptides are chemical messengers that are synthesized and released by nerve cells. Studies suggest that neuropeptides released from the nervous system in bone marrow may be involved in the regulation of hematopoiesis and survival of leukemic stem cells (LSC). Parathyroid hormone 2 receptor (PTH2R), a new LSC marker, is expressed on CD34 + leukemic cells. Its ligand, tuberoinfundibular peptide of 39 residues (TIP39), is expressed in the nervous system. However, the role of the TIP39-PTH2R axis in leukemic cells is unclear. We investigated the function of this axis in leukemic cell lines, as well as primary CD34 + myelodysplastic syndrome (MDS) and AML cells. Expression of PTH2R mRNA was higher in primary CD34 + MDS (GSE58831) or CD34 + CD38-AML (GSE24395) cells than in healthy volunteers. TIP39 reduced apoptosis in the leukemic cell lines Kasumi-1 and SKM-1. LC3-II expression was increased after incubation with TIP39, and was augmented in leukemic cell lines treated with lysosome inhibitors. This suggests that TIP39 could induce autophagy. Analysis of a public database (GSE58831) showed that high PTH2R expression was associated with poor overall survival and was an independent prognostic factor in MDS/AML patients. Our results suggest that the TIP39-PTH2R axis is a potential therapeutic target.